- Design, synthesis, and docking studies of novel benzimidazoles for the treatment of metabolic syndrome
-
In addition to lowering blood pressure, telmisartan, an angiotensin (AT1) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor γ (PPARγ). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPARγ active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPARγ agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT1 receptor with a Ki=13.4 nM, but it was devoid of PPARγ activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPARγ transactivation assay (69% activation) with no affinity for the AT1 receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARγ activity (29%) and affinity for the AT1 receptor (Ki=2.5 μM).
- Mizuno, Cassia S.,Chittiboyina, Amar G.,Shah, Falgun H.,Patny, Akshay,Kurtz, Theodore W.,Pershadsingh, Harrihar A.,Speth, Robert C.,Karamyan, Vardan T.,Carvalho, Paulo B.,Avery, Mitchell A.
-
supporting information; experimental part
p. 1076 - 1085
(2010/08/06)
-